? This study will attempt to map the chromosomal locations of genes underlying some of the neurocognitive traits that are known to be associated with schizophrenia and schizophrenia spectrum disorders. The neurocognitive traits, or endophenotypes, of greatest interest include impaired sensory gating as measured by the P50 auditory evoked potential, sustained focused attention, as measured by the continuous performance task, and working memory, as measured by computerized visuospatial tasks. The endophenotypes can be measured in normals and are expected to represent more proximal functions of gene action than the diagnosis of schizophrenia, thus facilitating the localization of their contributing loci. Our success in mapping genes for the endophenotypes does not depend on identification of individuals with extreme phenotypes but on the effect sizes of the genes contributing to normal variation in the endophenotypes in the population. The neurocognitive endophenotypes will be measured in a homogeneous, genetically isolated population in eastern Nepal, an ethnic group known as the Jirels. The study sample consists of 2000 individuals belonging to a single six-generation extended pedigree, from whom DNA has been collected and genotyping completed. The sample is the result of a complete ascertainment of four villages in the Jiri and Sikri valleys; all subjects were ascertained without regard to any disease status. Focusing on a large extended pedigree from an isolated and ethnically homogeneous population, and analyzing quantitative traits (the neurocognitive endophenotypes) by exploiting the power of variance components methods of analysis, will provide us with excellent power to map the relevant quantitative trait loci (QTLs). Mapping these traits in this population sample may identify genes that directly influence susceptibility to schizophrenia and other disorders and may even inform the search for genes that influence cognition. Even before the genes themselves are identified and cloned, the mapping of these correlated traits will aid and advance schizophrenia research in several ways. The neurophysiological trait data may be useful for objectively defining subtypes of the schizophrenia spectrum that are more etiologically homogeneous, and in general, aid in the refinement of schizophrenia spectrum nosology, relevant for genetic studies. In addition, the mapping of these correlated endophenotypes will enable more narrowly focused searches for additional susceptibility genes, and will also increase the power to identify additional genes influencing schizophrenia susceptibility, using conditional analyses. ? ?
